The skin commensal and opportunistic pathogen Staphylococcus epidermidis is an important cause of nosocomial infections. Virulence is attributable to formation of biofilm, which provides a microenvironment that protects the bacterium from attack by the host immune system and by chemotherapy. In this study we extended to S. epidermidis strategies previously aimed at treatment of S. aureus biofilms using photodynamic treatment (PDT) combined with chemotherapy or phagocytosis. A significant reduction in bacterial survival was observed when structurally distinct biofilms were exposed to the cationic porphyrin, tetra-substituted N-methyl-pyridyl-porphine (TMP), and simultaneously to visible light. Of note, the extent of biofilm clearance depended on its maturation stage: developing, young biofilms, were more sensitive towards PDT than mature biofilms. Furthermore, PDT-treated biofilms exposed to vancomycin or subjected to phagocytic action of whole blood were almost completely eradicated. The data we obtained establish that PDT combined with antibiotics or host defenses may also be a useful approach for the inactivation of S. epidermidis biofilms.